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1.
Oncologist ; 2022 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-35429394

RESUMO

BACKGROUND: Real-world (RW) evidence on nivolumab in pretreated patients with non-small cell lung cancer (NSCLC) by matching data from administrative health flows (AHFs) and clinical records (CRs) may close the gap between pivotal trials and clinical practice. METHODS: This multicenter RW study aims at investigating median time to treatment discontinuation (mTTD), overall survival (mOS) of nivolumab in pretreated patients with NSCLC both from AHF and CR; clinical-pathological features predictive of early treatment discontinuation (etd), budget impact (BI), and cost-effectiveness analysis were investigated; mOS in patients receiving nivolumab and docetaxel was assessed. RESULTS: Overall, 237 patients with NSCLC treated with nivolumab were identified from AHFs; mTTD and mOS were 4.2 and 9.8 months, respectively; 141 (59%) received at least 6 treatment cycles, 96 (41%) received < 6 (etd). Median overall survival in patients with and without etd were 3.3 and 19.6 months, respectively (P < .0001). Higher number, longer duration, and higher cost of hospitalizations were observed in etd cases. Clinical records were available for 162 patients treated with nivolumab (cohort 1) and 83 with docetaxel (cohort 2). Median time to treatment discontinuation was 4.8 and 2.6 months, respectively (P < .0001); risk of death was significantly higher in cohort 2 or cohort 1 with etd compared with cohort 1 without etd (P < .0001). Predictors of etd were body mass index <25, Eastern Cooperative Oncology Group performance status >1, neutrophile-to-lymphocyte ratio >2.91, and concomitant treatment with antibiotics and glucocorticoids. The incremental cost-effectiveness ratio of nivolumab was 3323.64 euros ($3757.37) in all patients and 2805.75 euros ($3171.47) for patients without etd. Finally, the BI gap (real-theoretical) was 857â188 euros ($969â050.18). CONCLUSION: We defined predictors and prognostic-economic impact of nivolumab in etd patients.

2.
Br J Cancer ; 2022 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-35264788

RESUMO

The possibility to analyse the tumour genetic material shed in the blood is undoubtedly one of the main achievements of translational research in the latest years. In the modern clinical management of advanced non-small cell lung cancer, molecular characterisation plays an essential role. In parallel, immunotherapy is widely employed, but reliable predictive markers are not available yet. Liquid biopsy has the potential to face the two issues and to increase its role in advanced NSCLC in the next future. The aim of this review is to summarise the main clinical applications of liquid biopsy in advanced non-small cell lung cancer, underlining both its potential and limitations from a clinically driven perspective.

3.
Cancer Immunol Immunother ; 71(4): 865-874, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34462870

RESUMO

BACKGROUND: The prognostic relevance of early immune-related adverse events (irAEs) in patients affected by non-small cell lung cancer (NSCLC) upon immunotherapy is not fully understood. METHODS: The Leading to Treatment Discontinuation cohort included 24 patients experiencing severe irAEs after one of two administrations of single anti-PD-1/PD-L1 in any line setting for metastatic NSCLC between November 2015 and June 2019. The control cohort was composed of 526 patients treated with single anti-PD-1/PD-L1 in any line setting with no severe irAE reported. The primary end points were median progression-free survival, overall survival, objective response rate, risk of progression of disease and risk of death. The correlation of clinic pathological features with early severe irAEs represented the secondary end point. RESULTS: Median PFS was 9.3 and 8.4 months, median OS was 12.0 months and 14.2 months at a median follow-up of 18.1 and 22.6 months in the LTD cohort and in the control cohort, respectively. The ORR was 40% (95% CI 17.2-78.8) in the LTD cohort and 32.7% (95% CI 27.8-38.2) in the control cohort. The risk of disease progression was higher in the LTD cohort (HR 2.52 [95% 1.10-5.78], P = .0288). CONCLUSIONS: We found no survival benefit in LTD cohort compared to the control cohort. However, early and severe irAEs might underly an immune anti-tumor activation. We identified a significant association with first-line immune checkpoints inhibitors treatment and good PS. Further studies on risk prediction and management of serious and early irAEs in NSCLC patients are needed.


Assuntos
Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/patologia , Receptor de Morte Celular Programada 1 , Estudos Retrospectivos
4.
JCO Oncol Pract ; 18(1): e20-e27, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34242052

RESUMO

PURPOSE: Novel organization models ensure early management of treatment-related adverse events (TRAEs) of new anticancer drugs. The aim of this prospective observational study was to evaluate the impact of the introduction of a nurse-led telephone triage (NTT) in reducing hospitalization of patients with cancer (CPs). PATIENTS AND METHODS: CPs on active medical treatment were educated to call the NTT in case of symptoms or TRAEs. Assessment of TRAEs was performed by trained oncology nurses according to the Common Terminology Criteria for Adverse Events grading scales and subsequent actions were taken according to the severity of the events. The primary end point of the study was to compare the rate of hospitalization of CPs on anticancer treatment after the introduction of NTT with that of the 2017-2018 period. RESULTS: From September 2018 to September 2019, a total of 1,075 patients received systemic anticancer treatment (v 936 patients in the same 2017-2018 period). Total consultations at NTT were 429 and 581 TRAEs were reported. Notably, 117 patients reported more than one TRAE. Common Terminology Criteria for Adverse Events were graded as G1 (237, 40.8%), G2 (231, 39.8%), or G3-4 (113, 19.4%). In the observation period, 109 CPs on treatment were hospitalized versus 138 in the 2017-2018 period with a normalized hospitalization rate of 10.1% versus 14.7% (P = .002 chi-square) with a reduction in normalized number of hospitalization of 44 and an estimated cost savings of 345,246 euros. CONCLUSION: The implementation of the NTT system in the clinical practice may help reducing the rates of hospitalization through the emergency room of CPs receiving modern medical treatments.


Assuntos
Neoplasias , Triagem , Humanos , Neoplasias/tratamento farmacológico , Papel do Profissional de Enfermagem , Encaminhamento e Consulta , Telefone
5.
Front Oncol ; 12: 840783, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35494084

RESUMO

Small cell lung cancer (SCLC) represents about 13%-15% of all lung cancers. It has a particularly unfavorable prognosis and in about 70% of cases occurs in the advanced stage (extended disease). Three phase III studies tested the combination of immunotherapy (atezolizumab, durvalumab with or without tremelimumab, and pembrolizumab) with double platinum chemotherapy, with practice-changing results. However, despite the high tumor mutational load and the chronic pro-inflammatory state induced by prolonged exposure to cigarette smoke, the benefit observed with immunotherapy is very modest and most patients experience disease recurrence. Unfortunately, biological, clinical, or molecular factors that can predict this risk have not yet been identified. Thanks to these clinically meaningful steps forward, SCLC is no longer considered an "orphan" disease. Innovative treatment strategies and combinations are currently under investigation to further improve the expected prognosis of patients with SCLC. Following the recent therapeutic innovations, we have reviewed the available literature data about SCLC management, with a focus on current unmet needs and potential predictive factors. In detail, the role of radiotherapy; fragile populations, such as elderly or low-performance status patients (ECOG PS 2), usually excluded from randomized studies; predictive factors of response useful to optimize and guide therapeutic choices; and new molecular targets and future combinations have been explored and revised.

6.
Expert Rev Clin Pharmacol ; 14(10): 1221-1232, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34114518

RESUMO

Introduction: Although standard doublet chemotherapy represents the upfront gold standard to increase survival and improve quality of life of gastric cancer patients, overall improvements in long-term outcomes are modest and novel treatments are urgently needed. Among these, immunotherapy is an increasingly attractive option.Areas covered: A number of clinical trials have shown that checkpoint inhibitors may be of value, but many unclear issues remain controversial and should be promptly untangled. In our short review, we offer the current available data regarding immunotherapies in gastric cancers, discuss potential limits of the reported trials, compare outcomes of checkpoints inhibitor to those of standard chemotherapy or other novel treatments, and present basic principles of immune surveillance and immune escape that may be embraced in the near future with novel drug combinations.Expert opinion: Gastric cancer patients may benefit from immunotherapy, both given alone in advanced lines and upfront in combination with chemotherapy. We believe that appropriate patients' and tumor's selection are crucial issues to maximize its potential efficacy. In addition, we think that assay standardization, biomarker agreement, and translational studies will improve the benefit-to-risk ratio of these agents in the clinical practice.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Imunoterapia/métodos , Neoplasias Gástricas/terapia , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Seleção de Pacientes , Qualidade de Vida , Neoplasias Gástricas/imunologia , Sobrevida
7.
Eur J Cancer ; 146: 145-154, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33607478

RESUMO

BACKGROUND: Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described in V600EBRAF-mutated (BRAFmt) metastatic colorectal cancers (mCRCs) but no data are available about its prognostic impact in this setting. METHODS: We assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAFmt mCRCs with matched clinical and pathological information. Tumours were dichotomized as synaptophysin high and low. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier and log-rank tests. RESULTS: Thirty-five tumours (22.0%) showed any level of positivity for synaptophysin, and 18 (11.3%) were characterized by positivity in at least 20% of tumour cells. Four cases resulted 100% synaptophysin positive. The histotype of synaptophysin-positive tumours (i.e. ≥20%) was not otherwise specified in 11 cases (61.1%) and mucinous adenocarcinoma in 4 cases (22.2%). Four cases were DNA mismatch repair deficient (22.2%) and 7 (38.9%) were characterized by a high number of tumour-infiltrating lymphocytes. At multivariate analysis, high synaptophysin expression was a negative independent prognostic factor for both PFS (HR = 2.00, 95% confidence interval [CI] 1.21-3.33, p = 0.006) and OS (HR = 2.27, 95% CI 1.35-3.85, p = 0.001). CONCLUSIONS: Among BRAFmt mCRCs, synaptophysin-positive tumours are characterized by worse PFS and OS. Further studies should investigate the molecular mechanisms involved in the acquisition of the neuroendocrine phenotype to identify novel-targeted treatment strategies.


Assuntos
Adenocarcinoma Mucinoso/patologia , Biomarcadores Tumorais/análise , Neoplasias Colorretais/patologia , Linfócitos do Interstício Tumoral/imunologia , Mutação , Sinaptofisina/genética , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/imunologia , Adenocarcinoma Mucinoso/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
8.
Transl Lung Cancer Res ; 10(1): 202-220, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33569305

RESUMO

BACKGROUND: Characterization of tumor-related genetic alterations is promising for the screening of new predictive markers in non-small cell lung cancer (NSCLC). Aim of the study was to evaluate prognostic and predictive role of most frequent tumor-associated genetic alterations detected in plasma before starting immune checkpoint inhibitors (ICIs). METHODS: Between January 2017 and October 2019, advanced NSCLC patients were prospectively screened with plasma next-generation sequencing (NGS) while included in two trials: VISION (NCT02864992), using Guardant360® test, and MAGIC (Monitoring Advanced NSCLC through plasma Genotyping during Immunotherapy: Clinical feasibility and application), using Myriapod NGS-IL 56G Assay. A control group of patients not receiving ICIs was analyzed. RESULTS: A total of 103 patients receiving ICIs were analyzed: median overall survival (OS) was 20.8 (95% CI: 16.7-24.9) months and median immune-related progression free disease (irPFS) 4.2 (95% CI: 2.3-6.1) months. TP53 mutations in plasma negatively affected OS both in patients treated with ICIs and in control group (P=0.001 and P=0.009), indicating a prognostic role. STK11 mutated patients (n=9) showed a trend for worse OS only if treated with ICIs. The presence of KRAS/STK11 co-mutation and KRAS/STK11/TP53 co-mutation affected OS only in patients treated with ICIs (HR =10.936, 95% CI: 2.337-51.164, P=0.002; HR =17.609, 95% CI: 3.777-82.089, P<0.001, respectively), indicating a predictive role. CONCLUSIONS: Plasma genotyping demonstrated prognostic value of TP53 mutations and predictive value of KRAS/STK11 and KRAS/STK11/TP53 co-mutations.

9.
Onco Targets Ther ; 13: 12027-12031, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33262603

RESUMO

Complex EGFR mutations are rare in non-small cell lung cancer (NSCLC). Limited clinical evidence is available on the efficacy of EGFR tyrosine kinase inhibitors (TKIs) in patients with NSCLC harbouring these uncommon EGFR mutations. Here, we reported the case of a complete metabolic response in a patient with advanced NSCLC carrying the uncommon EGFR G719A/V769M complex mutation treated with the first-line osimertinib.

10.
Ther Adv Med Oncol ; 12: 1758835920968463, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33224275

RESUMO

BACKGROUND: This prospective, multicentre, observational INVIDIa-2 study is investigating the clinical efficacy of influenza vaccination in advanced-cancer patients receiving immune-checkpoint inhibitors (ICIs), enrolled in 82 Italian centres, from October 2019 to January 2020. The primary endpoint was the incidence of influenza-like illness (ILI) until 30 April 2020. All the ILI episodes, laboratory tests, complications, hospitalizations and pneumonitis were recorded. Therefore, the study prospectively recorded all the COVID-19 ILI events. PATIENTS AND METHODS: Patients were included in this non-prespecified COVID-19 analysis, if alive on 31 January 2020, when the Italian government declared the national emergency. The prevalence of confirmed COVID-19 cases was detected as ILI episode with laboratory confirmation of SARS-CoV-2. Cases with clinical-radiological diagnosis of COVID-19 (COVID-like ILIs), were also reported. RESULTS: Out of 1257 enrolled patients, 955 matched the inclusion criteria for this unplanned analysis. From 31 January to 30 April 2020, 66 patients had ILI: 9 of 955 cases were confirmed COVID-19 ILIs, with prevalence of 0.9% [95% confidence interval (CI): 0.3-2.4], a hospitalization rate of 100% and a mortality rate of 77.8%. Including 5 COVID-like ILIs, the overall COVID-19 prevalence was 1.5% (95% CI: 0.5-3.1), with 100% hospitalization and 64% mortality. The presence of elderly, males and comorbidities was significantly higher among patients vaccinated against influenza versus unvaccinated (p = 0.009, p < 0.0001, p < 0.0001). Overall COVID-19 prevalence was 1.2% for vaccinated (six of 482 cases, all confirmed) and 1.7% for unvaccinated (8 of 473, 3 confirmed COVID-19 and 5 COVID-like), p = 0.52. The difference remained non-significant, considering confirmed COVID-19 only (p = 0.33). CONCLUSION: COVID-19 has a meaningful clinical impact on the cancer-patient population receiving ICIs, with high prevalence, hospitalization and an alarming mortality rate among symptomatic cases. Influenza vaccination does not protect from SARS-CoV-2 infection.

11.
Oncologist ; 25(12): e1996-e2005, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32557976

RESUMO

BACKGROUND: Targeted agents have improved the outcome of a subset of non-small cell lung cancer (NSCLC). Molecular profiling by next-generation sequencing (NGS) allows screening for multiple genetic alterations both in tissue and in plasma, but limited data are available concerning its feasibility and impact in real-world clinical practice. METHODS: Patients with advanced NSCLC consecutively referring to our Institution for potential eligibility to VISION trial (NCT02864992) were prospectively enrolled. They were already screened with standard method, and EGFR/ALK/ROS-1 positive cases were excluded. NGS was performed in plasma and tissue using the Guardant360 test covering 73 genes and the Oncomine Focus Assay covering 59 genes, respectively. RESULTS: The study included 235 patients. NGS was performed in plasma in 209 (88.9%) cases; 78 of these (37.3%) were evaluated also in tissue; tissue only was analyzed in 26 cases (11.1%). Half of the tissue samples were deemed not evaluable. Druggable alterations were detected in 13 (25%) out of 52 evaluable samples and 31 of 209 (14.8%) of plasma samples. Improved outcome was observed for patients with druggable alterations if treated with matched targeted agents: they had a longer median overall survival (not reached) compared with the ones who did not start any targeted therapy (9.1 months; 95% confidence interval, 4.6-13.6; p = .046). The results of NGS testing potentially also affected the outcome of patients treated with immunotherapy. CONCLUSION: Systematic real-life NGS testing showed the limit of tissue analysis in NSCLC and highlighted the potentiality of genetic characterization in plasma in increasing the number of patients who may benefit from NGS screening, both influencing the clinical decision-making process and affecting treatment outcome. IMPLICATIONS FOR PRACTICE: Genetic characterization of cancer has become more important with time, having had positive implications for treatment specificity and efficacy. Such analyses changed the natural history of advanced non-small cell lung cancer (aNSCLC) with the introduction of drugs targeted to specific gene alterations (e.g., EGFR mutations, ALK and ROS-1 rearrangements). In the field of cancer molecular characterization, the applicability of the analysis of a wide panel of genes using a high-throughput sequencing approach, such as next-generation sequencing (NGS), is still a matter of research. This study used NGS in a real-world setting to systematically and prospectively profile patients with aNSCLC. The aim was to evaluate its feasibility and reliability, as well as consequent access to targeted agents and impact on clinical outcome whenever a druggable alteration was detected either in tumor tissue samples or through liquid biopsy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Preparações Farmacêuticas , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Reprodutibilidade dos Testes
12.
Expert Opin Biol Ther ; 20(3): 319-326, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32011207

RESUMO

Background: Immune-checkpoint inhibitors have radically changed the treatment landscape of Non-Small-Cell Lung Cancer (NSCLC). It is still unclear whether specific clinical characteristics might identify those patients benefiting from immunotherapy more than others. The aim of this study was to identify clinical characteristics associated with disease-specific survival (DSS), time-to-treatment failure (TTF), objective responses (OR) and progressive disease (PD) in NSCLC patients treated with Nivolumab.Methods: This was a multicenter retrospective study conducted on 294 patients treated with Nivolumab for advanced NSCLC.Results: Of the more than 50 variables analyzed, five showed a significant correlation with DSS: ECOG PS, size of the biggest brain metastasis, number of metastatic sites, toxicity, and malignant pleural effusion. Three variables significantly correlated with TTF: malignant pleural effusion, number of metastatic sites, number of liver metastases. Malignant pleural effusion was the only variable showing a significant correlation with OR, as well as the only one correlating with all the endpoints of the study.Conclusions: This study identified clinical characteristics associated with survival and response during treatment with Nivolumab in NSCLC patients. The unfavorable association between malignant pleural effusion and objective response is a novel finding with important translational implications.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Adulto , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Derrame Pleural Maligno/complicações , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
13.
Adv Ther ; 37(3): 1145-1155, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32002809

RESUMO

INTRODUCTION: Immune checkpoint inhibitors have provided substantial benefit in non-small cell lung cancer (NSCLC) with unprecedented results in terms of survival. However, the identification of reliable predictive biomarkers to these agents is lacking and multiple clinicopathological factors have been evaluated. The aim of this study was to analyze the potential role of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lactate dehydrogenase (LDH) levels in patients with pretreated NSCLC receiving nivolumab. METHODS: This was a retrospective multicenter study involving 14 Italian centers, evaluating the role of some laboratory results in patients with NSCLC treated with nivolumab in the second or later lines of therapy for at least four doses and with a disease re-staging. RESULTS: A total of 187 patients with available pretreatment laboratory results were included. NLR levels below 5 were associated with an improvement in terms of both progression-free survival (PFS) (p = 0.028) and overall survival (OS) (p = 0.001), but not in terms of overall response rate (ORR) or disease control rate (DCR). Moreover, PLR levels below 200 were associated with longer PFS (p = 0.0267) and OS (p = 0.05), as well as higher ORR (p = 0.04) and DCR (p = 0.001). In contrast, LDH levels above the upper normal limit (UNL) were not associated with significant impact on patient outcomes. CONCLUSIONS: Patients with pretreated NSCLC and high pretreatment levels of NLR and PLR may experience inferior outcomes with nivolumab. Therefore, in this subgroup of patients with poor prognosis the use of alternative therapeutic strategies may be a valuable option, especially in programmed cell death ligand 1 (PD-L1)-negative patients and/or in the presence of other additional poor prognostic factors.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Leucócitos/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neutrófilos/metabolismo , Nivolumabe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/sangue , Feminino , Humanos , Contagem de Leucócitos , Neoplasias Pulmonares/sangue , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
14.
Br J Cancer ; 121(7): 593-599, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31474758

RESUMO

BACKGROUND: V600EBRAF mutated metastatic colorectal cancer (mCRC) is a subtype (10%) with overall poor prognosis, but the clinical experience suggests a great heterogeneity in survival. It is still unexplored the real distribution of traditional and innovative biomarkers among V600EBRAF mutated mCRC and which is their role in the improvement of clinical prediction of survival outcomes. METHODS: Data and tissue specimens from 155 V600EBRAF mutated mCRC patients treated at eight Italian Units of Oncology were collected. Specimens were analysed by means of immunohistochemistry profiling performed on tissue microarrays. Primary endpoint was overall survival (OS). RESULTS: CDX2 loss conferred worse OS (HR = 1.72, 95%CI 1.03-2.86, p = 0.036), as well as high CK7 expression (HR = 2.17, 95%CI 1.10-4.29, p = 0.026). According to Consensus Molecular Subtypes (CMS), CMS1 patients had better OS compared to CMS2-3/CMS4 (HR = 0.37, 95%CI 0.19-0.71, p = 0.003). Samples showing less TILs had worse OS (HR = 1.72, 95%CI 1.16-2.56, p = 0.007). Progression-free survival analyses led to similar results. At multivariate analysis, CK7 and CMS subgrouping retained their significant correlation with OS. CONCLUSION: The present study provides new evidence on how several well-established biomarkers perform in a homogenousV600EBRAF mutated mCRC population, with important and independent information added to standard clinical prognosticators. These data could be useful to inform further translational research, for patients' stratification in clinical trials and in routine clinical practice to better estimate patients' prognosis.


Assuntos
Fator de Transcrição CDX2/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Queratina-7/metabolismo , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Biomarcadores Tumorais/metabolismo , Fator de Transcrição CDX2/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Proteínas do Citoesqueleto/metabolismo , Feminino , Deleção de Genes , Genes MCC , Humanos , Queratina-20/metabolismo , Linfócitos do Interstício Tumoral , Masculino , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/metabolismo , Prognóstico , Análise Serial de Tecidos
16.
Eur J Cancer ; 118: 121-130, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31330487

RESUMO

BACKGROUND: Despite the well-known negative prognostic value of the V600EBRAF mutation in patients with metastatic colorectal cancer (mCRC), its outcome is quite heterogeneous, and the basis for this prognostic heterogeneity should be better defined. METHODS: Two large retrospective series of V600EBRAF-mutated mCRC from 22 institutions served as an exploratory and validation set to develop a prognostic score. The model was internally and externally validated. RESULTS: A total of 395 V600EBRAF-mutated mCRCs were included in the exploratory set. Performance status, CA19.9, lactate dehydrogenase, neutrophil/lymphocyte ratio, grading and liver, lung and nodal involvement emerged as independent prognostic factors for overall survival (OS). Two different scoring systems were built: a 'complete' score (0-16) including all significant covariates and a 'simplified' score (0-9), based only on clinicopathological covariates, and excluding laboratory values. Adopting the complete score, proportions of patients with a low (0-4), intermediate (5-8) and high (9-16) score were 44.7%, 42.6% and 12.6%, respectively. The median OS was 29.6, 15.5 (hazard ratio [HR] for intermediate vs low risk: 2.16, 95% confidence interval [CI]: 1.44-3.22, p < .001) and 6.6 months (HR for high vs low risk: 4.72, 95% CI: 2.72-8.20, p < .001). Similar results were observed also after adjusting for the type of first-line treatment and adopting the simplified score. The simplified prognostic score derived from the exploratory set was then applied to the validation set for external confirmation. CONCLUSIONS: These scoring systems are based on easy-to-collect data and defined specific subgroups with relevant differences in their life expectancy. These tools could be useful in clinical practice, would allow better stratification of patients in clinical trials and may be adopted for proper adjustments in exploratory translational analyses.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Análise Mutacional de DNA , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Feminino , Predisposição Genética para Doença , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Adulto Jovem
17.
Oncologist ; 24(8): 1128-1136, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31015312

RESUMO

BACKGROUND: Immune-checkpoint inhibitors (ICIs) are now standard of care for advanced non-small cell lung cancer (NSCLC). Unfortunately, many patients experience immune-related adverse events (irAEs), which are usually mild and reversible, but they require timely management and may be life threatening. No predictive markers of irAEs are available. MATERIALS AND METHODS: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were evaluated in patients with NSCLC consecutively treated with ICIs. Prespecified cutoff values of NLR and PLR were used and related to outcome and onset of irAEs. A control group of patients with advanced NSCLC not receiving ICIs was included. RESULTS: The study included 184 patients: 26 (14.1%) received pembrolizumab upfront, and 142 (77%) received ICIs (pembrolizumab, nivolumab or atezolizumab) after one or more lines of chemotherapy. The median number of ICIs cycles was six (range, 1-61). The median progression-free survival and overall survival were 4.8 (95% CI, 3.4-6.3) and 20.6 (95% CI, 14.7-26.5) months, respectively. Sixty patients (32.6%) developed irAEs, mainly grade 1-2 (65.0%), causing ICI interruption in 46 cases (25.0%). Low NLR and low PLR at baseline were significantly associated with the development of irAEs (odds ratio [OR], 2.2; p = .018 and OR, 2.8; p = .003, respectively). Multivariate analyses confirmed PLR as independent predictive marker of irAEs (OR, 2.3; p = .020). CONCLUSION: NLR and PLR may predict the appearance of irAEs in non-oncogene-addicted aNSCLC, although this conclusion warrants prospective validation. IMPLICATIONS FOR PRACTICE: This study was designed to investigate the role of blood biomarkers in predicting the occurrence of immune-related adverse events (irAEs) in patients with advanced non-small cell lung cancer receiving immunotherapy. The results of the study suggest a potential predictive role of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as markers for irAE development in this category of patients. These data provide rationale for an easy and feasible application to be validated in clinical practice.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Neoplasias Pulmonares/tratamento farmacológico , Neutrófilos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Contagem de Plaquetas , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Estudos Retrospectivos , Medição de Risco/métodos
18.
Oncologist ; 24(6): e318-e326, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30846513

RESUMO

INTRODUCTION: Gefitinib, erlotinib, and afatinib represent the approved first-line options for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Because pivotal trials frequently lack external validity, real-world data may help to depict the diagnostic-therapeutic pathway and treatment outcome in clinical practice. METHODS: MOST is a multicenter observational study promoted by the Veneto Oncology Network, aiming at monitoring the diagnostic-therapeutic pathway of patients with nonsquamous EGFR-mutant NSCLC. We reported treatment outcome in terms of median time to treatment failure (mTTF) and assessed the impact of each agent on the expense of the regional health system, comparing it with a prediction based on the pivotal trials. RESULTS: An EGFR mutation test was performed in 447 enrolled patients, of whom 124 had EGFR mutation and who received gefitinib (n = 69, 55%), erlotinib (n = 33, 27%), or afatinib (n = 22, 18%) as first-line treatment. Because erlotinib was administered within a clinical trial to 15 patients, final analysis was limited to 109 patients. mTTF was 15.3 months, regardless of the type of tyrosine kinase inhibitor (TKI) used. In the MOST study, the budget impact analysis showed a total expense of €3,238,602.17, whereas the cost estimation according to median progression-free survival from pivotal phase III trials was €1,813,557.88. CONCLUSION: Good regional adherence and compliance to the diagnostic-therapeutic pathway defined for patients with nonsquamous NSCLC was shown. mTTF did not significantly differ among the three targeted TKIs. Our budget impact analysis suggests the potential application of real-world data in the process of drug price negotiation. IMPLICATIONS FOR PRACTICE: The MOST study is a real-world data collection reporting a multicenter adherence and compliance to diagnostic-therapeutic pathways defined for patients with epidermal growth factor receptor-mutant non-small cell lung cancer. This represents an essential element of evidence-based medicine, providing information on patients and situations that may be challenging to assess using only data from randomized controlled trials, e.g., turn-around time of diagnostic tests, treatment compliance and persistence, guideline adherence, challenging-to-treat populations, drug safety, comparative effectiveness, and cost effectiveness. This study may be of interest to various stakeholders (patients, clinicians, and payers), providing a meaningful picture of the value of a given therapy in routine clinical practice.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Procedimentos Clínicos/estatística & dados numéricos , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Afatinib/economia , Afatinib/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/economia , Carcinoma Pulmonar de Células não Pequenas/genética , Análise Custo-Benefício , Procedimentos Clínicos/normas , Análise Mutacional de DNA/normas , Análise Mutacional de DNA/estatística & dados numéricos , Progressão da Doença , Intervalo Livre de Doença , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/economia , Cloridrato de Erlotinib/uso terapêutico , Feminino , Seguimentos , Gefitinibe/economia , Gefitinibe/uso terapêutico , Fidelidade a Diretrizes/normas , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/economia , Neoplasias Pulmonares/genética , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Mutação , Guias de Prática Clínica como Assunto , Intervalo Livre de Progressão , Estudos Prospectivos , Inibidores de Proteínas Quinases/economia , Fatores de Tempo , Falha de Tratamento
19.
Br J Cancer ; 120(5): 522-526, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30745584

RESUMO

BACKGROUND: HER2 is the only validated predictive biomarker in gastro-oesophageal carcinoma (GOC). However, several factors, such as heterogeneity in protein expression, shortage of evaluable tumour tissue and need for quick target assessment, underline the usefulness of a pre-screening tool in order to anticipate HER2 status. METHODS: Data from 723 consecutive GOC analysed for HER2 at four Italian Institutions were collected. HER2 positivity was defined as 3+ by immunohistochemistry (IHC) or 2+ with gene amplification by in situ hybridisation (ISH). A multivariate logistic regression model was built using data from 413 cases, whereas 310 patients served as validation cohort. C-index, visual inspection of the calibration plot, Brier score and Spiegelhalter z-test were used to assess the performance of the nomogram. RESULTS: HER2 positive rate was 17.4%. Four variables were retained after adjustment in the final model: grading, Lauren's histotype, pathologic material analysed (surgical specimen/biopsy) and site of tissue collection (primary tumour/metastases). Visual inspection of the calibration plot revealed a very good overlap between predicted and observed probabilities, with a Brier score of 0.101 and a non-significant Spiegelhalter z-test (P = 0.319). C-index resulted in 0.827 (95%CI 0.741-0.913). CONCLUSION: A simple nomogram based on always-available pathologic information accurately predicts the probability of HER2 positivity in GOC.


Assuntos
Carcinoma/metabolismo , Junção Esofagogástrica/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma/tratamento farmacológico , Feminino , Amplificação de Genes , Humanos , Imuno-Histoquímica , Modelos Logísticos , Masculino , Análise Multivariada , Nomogramas , Reprodutibilidade dos Testes , Neoplasias Gástricas/tratamento farmacológico , Trastuzumab/uso terapêutico
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